DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 23–3
Oral Medications for Treating Alcohol Abuse
MEDICATION USUAL DOSE MECHANISM/EFFECT
Disulfiram 250 mg/day Inhibits ALDH with resulting ↑ acetaldehyde
(range 125-500 mg/day) after drinking. Abstinence is reinforced to
avoid the resulting adverse reaction.
Naltrexone 50 mg/day μ opioid receptor antagonist; felt to ↓
drinking through ↓ feelings of reward with
alcohol and/or ↓ craving.
Acamprosate 666 mg three times daily Weak antagonist of NMDA receptors,
activator of GABA A
receptors; may ↓ mild
protracted abstinence syndromes with ↓
feelings of a “need” for alcohol.
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“cure” for alcoholism and does not prevent relapse in all patients.
Naltrexone works best when used in conjunction with some form of
psychosocial therapy, such as cognitive behavioral therapy (Anton
et al., 1999). It typically is administered after detoxification and given
at a dose of 50 mg/day for several months. Adherence to the regimen
is important to ensure the therapeutic value of naltrexone and has
proven to be a problem for some patients. The most common side
effect of naltrexone is nausea, which is more common in women
than in men and subsides if the patients abstain from alcohol. When
given in excessive doses, naltrexone can cause liver damage. It is
contraindicated in patients with liver failure or acute hepatitis and
should be used only after careful consideration in patients with active
liver disease.
Nalmefene (REVEX) is another opioid antagonist that appears
promising in preliminary clinical tests (Mason et al., 1999). It has
a number of advantages over naltrexone, including greater oral bioavailability,
longer duration of action, and lack of dose-dependent
liver toxicity.
Acamprosate
Acamprosate (N-acetylhomotaurine; CAMPRAL) is an
analogue of GABA.
O
N
HO S
H
O
ACAMPROSATE
A number of double-blind, placebo-controlled studies have
demonstrated that acamprosate (1.3-2 g/day) decreases drinking frequency
and reduces relapse drinking in abstinent alcoholics and
appears to have efficacy similar to that of naltrexone. Studies in laboratory
animals have shown that acamprosate decreases alcohol
intake without affecting food or water consumption. Acamprosate
generally is well tolerated by patients, with diarrhea being the main
side effect (Garbutt et al., 1999). No abuse liability has been noted.
The drug undergoes minimal metabolism in the liver, is excreted primarily
by the kidneys, and has an elimination t 1/2
of 18 hours after
O
oral administration. Concomitant use of disulfiram appears to
increase the effectiveness of acamprosate, without any adverse drug
interactions being noted (Besson et al., 1998).
Disulfiram
Disulfiram (tetraethylthiuram disulfide; ANTABUSE) was
ingested in the course of an investigation of its potential
anthelminthic efficacy by two Danish physicians,
who became ill at a cocktail party and were quick to
realize that the compound had altered their responses
to alcohol. They initiated a series of pharmacological
and clinical studies that provided the basis for the use
of disulfiram as an adjunct in the treatment of chronic
alcoholism. Similar responses to alcohol ingestion are
produced by various congeners of disulfiram, namely,
cyanamide, the fungus Coprinus atramentarius, the
hypoglycemic sulfonylureas, metronidazole, and certain
cephalosporins.
N
S
S S S
DISULFIRAM
Disulfiram, given alone, is a relatively nontoxic substance,
but it inhibits ALDH activity and causes the blood acetaldehyde concentration
to rise to 5-10 times above the level achieved when
ethanol is given to an individual not pretreated with disulfiram.
Acetaldehyde, produced as a result of the oxidation of ethanol by
ADH, ordinarily does not accumulate in the body because it is further
oxidized almost as soon as it is formed. Following the administration
of disulfiram, both cytosolic and mitochondrial forms of
ALDH are irreversibly inactivated to varying degrees, and the concentration
of acetaldehyde rises. It is unlikely that disulfiram itself
is responsible for the enzyme inactivation in vivo; several active
N
ETHANOL AND METHANOL